Federal Smallpox Immunization Policy - A Short Critique

On September 23, 2002, the CDC released its "Smallpox Vaccination Clinic
Guide" (Guide) a part of the upcoming revisions of the "CDC
Smallpox Response Plan and Guidelines" (Plan). (See http://biotech.law.lsu.edu/blaw/bt/smallpox.htm)
The Guide sets out the operating parameters for clinics participating in a mass
immunization campaign, either in specific regions or as part of a national campaign.
Mass immunization is to be a back up to the selective case-finding and immunization
(Ring) strategy which would only immunize contacts and contacts of contacts,
but would not involve mass immunization of a community. This is a welcome document,
but one that leaves very important questions unanswered. I will briefly review
the general problems related to smallpox spread and immunization strategies,
then review the extent to which this Guide and the CDC plan address these issues.

SMALLPOX

Smallpox was one of the great scourges of mankind. It is a rapidly progressive
disease that causes ulceration of the skin and affects other organs in the body,
in particular the mouth and throat. It has a 2 week incubation period before
the victim develops visible lesions, then the disease runs its course in another
week or so. If the victim survives, he or she will be scarred by the ulcers
on the skin, hence the name smallpox from these pock marks. The disease is spread
by contact with the sores, which exude virus, or through the respiratory spread
of virus as the throat and mouth become infected and the victim coughs up virus.
The virus particles are relatively stable and will persist on clothing and other
materials which the victim has been in contact with. Well before the germ theory
was developed, it was understood that smallpox infected corpses and clothing
that had been in contact with smallpox victims could spread the infection. Early
biological warfare saw corpses hurled into towns during sieges and infected
clothing given to tribes during some of the Indian wars in North America.

The key medical facts about smallpox are that:

1) it has a high infectivity, i.e., if a person with no immunity is exposed
to the virus, there is a high probability he or she will be infected;

2) it can be infectious for a few days before there are obvious skin lesions;

3) the disease or immunization for it leaves a person immune from infection
for 20 or more years;

4) the disease kills about 30% of infected persons, although it is possible
this would be lower if intensive medical support were available;

5) the vaccine is a live virus vaccine with the risks attendant to live virus
vaccines - while the virus is vaccinia and not smallpox, it can become virulent
in immunosuppressed persons;

6) the patient lives or dies within 3 weeks and there is no animal host,
which means that effective control measures can rapidly stop the disease;
and

7) vaccinating a person after exposure, even a few days after, will still
prevent disease in most cases.

Post World War II, there was a world-wide effort to eradicate smallpox. By
the 1960s smallpox was limited to a few areas of the world and by the early
1970s many countries, including the U.S., stopped routine smallpox immunizations.
The last case of naturally occurring smallpox was observed in 1977. (MMWR
describing the last case.) While a few selected individuals in health care,
research, and the military continued to receive immunizations through the 1980s,
the general population of the U.S. was either born after 1970 and not immunized
or has not be re-immunized for 30 or more years and has only questionable immunity.
This is true of the rest of the world as well. Thus, for the first time in human
history, most of the population of the word is susceptible to a fast spreading,
fatal communicable disease. Ironically, modern technology has put the entire
world in the same position as the indigenous peoples in the Americas and the
Pacific islands facing the first European explorers and their diseases.

This vulnerability was recognized by all smallpox experts and fueled a debate
in the 1990s as to whether the last stocks of virus, maintained at the CDC and
by the Russians, should be destroyed, lest they fall into terrorist hands. Unknown
to these experts, the Russians were making tons of smallpox as a biological
weapon. This came to light in 1993, but intelligence forces did not make the
information generally available for some years later. The existence of this
store, and the inability of the Russians to convincingly account for it, made
discussions of destroying the last virus stocks moot. It should have made finding
a genetically engineered virus fragment vaccine the first priority, but this
research has only been started recently because of the delay in admitting that
the Russians had uncontrolled stocks of virus.

THE IMMUNIZATION IMPERATIVE

Since 9/11 and the subsequent anthrax letters, preparing for bioterrorism has
been a key part of the war on terrorism. Smallpox has to be considered as the
most dangerous agent, if not the most likely one, and the only protection against
smallpox is immunization.

The federal government has been incrementally refining its smallpox immunization
strategy, and this discussion is based on the policy as of 25 September 2002.

The first proposal had two parts:

1) staged immunization of health care and emergency workers, starting with
first responders to bioterrorism and working through to routine medical care
workers; and

2) ring immunizations in the case of an outbreak.

Ring immunization strategy was developed during the smallpox eradication campaign
in the 1960s and 1970s. You identify cases, which is easy to do because the
disease is so visible. Then you isolate the case and immunize everyone who had
contact with the case and everyone who had contact with the contacts. (Despite
the revisionist history about protecting everyone's rights, this was sometimes
brutal and involved bribing informers and vaccinating people without much nicety
as regards consent, not to mention the isolation issues. This is not a criticism,
it had to be done that way, but we should not pretend that it was otherwise.)

This works great when you have small villages in Africa or India and you are
doing clean up in a mostly immune population that you can vaccinate and isolate
with no concerns about their rights. It is harder to imagine this strategy in
a US city - how do you do a ring immunization strategy for someone who rides
downtown on the subway, shops in a mall at lunch, then goes to the office in
a high rise building? Two rings and you have most of the city.

The most politically difficult assumption behind this plan is that the government
is going to be able to sit on the vaccine and control who gets it if there is
an outbreak or even a suspected outbreak. It will be politically impossible
to deny the general public access to vaccine if there is smallpox outbreak or
scare. If there is an outbreak, the hardest political decision that any president
has faced will come up: do I really trust this ring system, or do I allow mass
immunizations? The potential risks to the nation of using the ring system and
having it fail are enormous, and the political risks are incalculable because
sticking to the ring strategy will mean ignoring the public outcry for vaccine.
There is little chance that the government will be able to avoid mass immunization
of the U.S. population. With this political reality in mind, the CDC has just
released a plan for mass immunization clinics, for either cities or the entire
U.S. The objective, as reported in some news accounts, is to be able to immunize
the entire population in a few days. These plans are sound approaches to the
smallpox immunization problem as it existed in the United States in 1971. They
do not address the key problems of 2002.

BACK IN TIME TO 1971

In fall 1971, the Clinical Research Service at Texas Children's hospital in
Houston did the first grand experiment in human immunosuppression - they created
the Bubble Baby. David's parents had a sex-linked genetic disease that lead
their male children to be born with no immune system. David had a brother who
was born earlier and died from the disease, alerting the physicians. The plan
was to put David into a sterile environment at birth to see if he would develop
an immune system if he could be kept alive for some months. In retrospect, there
should have been more thought about what would happen if he did not, but that
is easy to say after the fact. I joined this service a year or so later as a
grad student. We learned a tremendous amount about a very rare and poorly understood
condition - immunosuppression - from David.

I tell this tale to illustrate a point: we have lived with the medical fact
of immunosuppression secondary to HIV, cancer and arthritis treatment, transplants,
and other natural and iatrogenic causes for more than 20 years, and almost everyone
implicitly thinks this is the way it has always been. When we did the last massive
smallpox vaccine campaigns in the US, we had almost no immunosuppressed persons
in the population. (Partially because they probably were the 1/1,000,000 deaths
from the vaccine.)

THE REALITY OF IMMUNOSUPPRESSION

In 2002, there are at least 1% and perhaps 2% or more of the population with
significant immunosuppression, either permanently or because their physician
likes to treat aches and pains with Medrol Dosepaks. Smallpox immunizations
pose three problems for immunosuppressed persons. First, they may not develop
effective immunity. This leaves them susceptible to smallpox and a threat to
others who are not immune. Second, they are at significant risk of disseminated
vaccinia if vaccinated or exposed through contact with a recently vaccinated
person who has picked at his/her vaccine sore. Disseminated vaccinia means that
the normally benign vaccinia virus used in smallpox vaccine becomes virulent
because of the patient's weakened immune system. This is a common phenomena
in immunosuppressed persons in which normally benign organisms such as Pneumocystis
carinii become serious pathogens. While disseminated vaccinia only poses a risk
of contagion to other immunosuppressed persons, it is a serious disease with
almost the same morbidity and mortality as smallpox, and a more prolonged course.

Working the numbers, 1% of 280,000,000 is 2,800,000 immunosuppressed persons.
If 1/10, a conservative estimate, develop vaccine complications, that is 280,000,
and if only 1/10 of those die or are permanently injured, that is 28,000, probably
on the low side. The numbers that the press and the government documents continue
to use are those from the 1960s world, 1/1,000,000 deaths and perhaps 10/1,000,000
serious complications. These translate to 280 deaths and 2,800 serious complications,
numbers that can only be reconciled with 28,000 deaths and 280,000 complications
by one assumption: that no immunosuppressed persons will be immunized. Consistent
with this, the CDC's smallpox vaccine guidelines, prior to the most recent mass
immunization clinic guidelines, recommend that immunosuppressed persons not
be vaccinated.

Many, probably most, persons do not know they are immunosuppressed, either
because they do not know they have HIV or because they have no idea of the connection
between the drugs they are taking and immunosuppression. The first issue posed
by non-emergency smallpox immunizations is identifying the immunosuppressed.
The guidelines depend on self-identification, which may be impossible either
because the patient does not know or because the patient is unwilling to admit
his/status because it is linked to HIV. The second issue is whether persons
who refuse immunizations must be removed from all first responder teams and,
if there is an outbreak, barred from working in any capacity that would put
them in contact with exposed persons. This would exclude them from health care,
police, fire, and many other activities. Such exclusion may be critical to public
health and safety since unimmunized persons pose a risk to themselves and others,
but it is it supportable politically? None of these questions is adequately
addressed in the government's recommendations on immunizing health care and
emergency workers.

Ring strategy immunizations after a case of smallpox pose these questions more
starkly. Persons who cannot be successfully immunized must be quarantined. The
guidelines on mass immunizations recommend that such persons be quarantined
for 18 days. The guidelines on quarantine facilities, however, state that only
immunized persons should be put in quarantine facilities because of the chance
of a missed diagnosis and because of the chance of contagion from others. More
tellingly, Guide C - Isolation and Quarantine Guidelines, the CDC official guideline,
does not mention immunosuppression or HIV a single time. Where should these
persons go? Can they be put in the quarantine facilities, knowing that they
are at high risk for smallpox should anyone in the facility develop the disease?
Should they be vaccinated, knowing that they have a high risk of disseminated
vaccinia?

Mass immunizations, in response to a case of smallpox, make all of these problems
intractable. The number of quarantine beds suitable for isolating a case of
smallpox is very small nationally. Even the largest cities have only a hand
full of such beds. Isolation rooms used for cancer and transplant patients cannot
be used because they are designed to protect the patient from others, not others
from the patient. Converted motels and hotels have no effective air flow isolation,
so anyone who is not immunized will become infected if any other quarantined
persons become infected. Most critically, there will be no time to sort out
who is immunosuppressed from those who are not. Immunosuppressed persons will
feel tremendous pressure to accept immunization and avoid the pest house. Since
the plan is to carry out the immunizations in short period, the immunizations
will be done before any of the complications develop. When they do develop,
they will all develop at the same time, potentially swamping the ability of
the medical system to provide care.

WHAT SHOULD WE BE DOING?

The number one opportunity has been missed - in 1993, when were knew the Soviets
had an uncontrolled stockpile of smallpox, we should have started work on a
genetically engineered vaccine that did not use live virus. We can wait until
such a vaccine is available, and run the risk of an outbreak. In an outbreak,
the risk of infection spreading in the general population and killing tens of
millions means that we will have to immunize everyone with little regard for
their individual risk. Preventing 10,000,000 deaths at the cost of 28,000 is
simple arithmetic.

A gradual mass immunization of the entire population before there is an outbreak
may be the best way to protect the public health and the rights of individuals.
Such a program would allow time to identify the immunosuppressed so they are
not forced to choose immunization or the pest house. It would also let us learn
more about the risks of the vaccine as persons with various levels of immunosuppression
chose to be immunized, and it would mean that those with complications could
receive optimum medical treatment. This strategy would be a logical extension
of the government's staged immunization of health care and emergency workers.
If, at the end of campaign, several % of the population was unimmunized, there
would still be enough herd immunity to make managing an outbreak possible.

Before such a campaign is started, the government must figure out how to pay
for the care of persons with complications, and how to deal with the problem
of excluding unimmunized persons from certain jobs. It is critical that Congress
do this with specific legislation and that this legislation completely eliminate
tort litigation over vaccine complications. Ideally there will be a government
compensation fund with pre-established guidelines, and, for those who want more
coverage, perhaps the opportunity to purchase private vaccination insurance.
Given the probable level of vaccine complications, litigation would cripple
the public health system.